This application responds to RFA OD-08-001 Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network and proposes the renewal of U54 # NS059065 Nervous System Channelopathies: Pathogenesis and Treatment, focusing on the prototypic episodic disorders periodic paralysis, episodic ataxia and nondystrophic myotonia. It exploits the strengths of 10 collaborating centers in 4 countries to link molecular scientists with clinical investigators experienced in the development of new treatments for neurological disease. The training plan builds on the successful mentoring skills of translational scientists to develop a cadre of patient-oriented investigators prepared for careers in rare disease research. The Clinical Investigation of Neurologic Channelopathies (CINCH) has mutually supportive relationships with US and international patient advocacy groups: the MDA's of the US, Canada, and UK;the National Ataxia Foundation;and the international Periodic Paralysis Association. 4 US CINCH centers have recently funded CTSAs;the other 2 have CRCs (CTSA's pending). In the UK the National Hospital Queens Square investigator has one of 6 newly-funded translational Research Centers providing a rich infrastructure for research and training including the support of year-out medical student trainees. New CINCH projects will address the development of validated therapeutic targets in episodic disorders with innovative trial designs using novel patient-reported outcome measures piloted in the initial 6 years to better characterize episodic phenotypes and to devise treatments for Andersen-Tawil syndrome, other periodic paralysis patients currently without treatment options, and episodic ataxia-1. Companion studies funded by other grants will characterize the physiologic implications of channel dysfunction, identify the risk/triggering factors for the intermittent, recurrent symptoms, and collaborate with industry partners to bring new therapeutic agents to market. Insights from CINCH investigations hold promise for providing a window for a better understanding of many other episodic Channelopathies such as epilepsy and migraine;CINCH trainees will be well-positioned to pursue innovative treatments for both rare and more common diseases. PUBLIC HEALTH RELEVANCE: This proposal builds on the longitudinal and therapeutic clinical studies that were initiated in the initial funding cycle. Phase 1,2 clinical trials for neuromuscular Channelopathies are employing novel outcome measures to establish treatment and working with industry partners and patient advocacy groups to successfully bring treatment to patients.